Thrombotic complications of atherosclerotic vascular disease are mediated by both platelet-dependent mechanisms and tissue factor-mediated activation of the coagulation system. Platelet-rich thrombosis in response to atherosclerotic plaque rupture is a critical determinant of the clinical manifestations of atherosclerotic vascular disease (e.g., unstable angina, myocardial infarction) and the vascular wall response to injury (e.g., intimal hyperplasia). The central hypothesis of this proposal is that thrombus-associated procoagulants, primarily thrombin bound to fibrin and factor Xa/Va complex bound to phospholipids, are critical determinants of the progression of thrombosis and designed to characterize molecular mechanisms responsible for thrombus-associated procoagulant activity, and to define the extent to which attenuation or potentiation of clot-associated procoagulant activity in vivo influences the progression of thrombosis and the response to antithrombotic interventions. To accomplish these objectives, the molecular determinants of thrombus-associated procoagulant activity will be defined, including mechanisms involved in the binding of thrombin and Xa/Va to whole blood thrombi, determinants of the activity of thrombus- associated factor Xa/Va, and the interactions between thrombus-associated thrombin, Xa/Va, and the platelets in the regulation of local thrombin activity.